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A Single-blind, Placebo-controlled, Dose-ranging Trial Of Oral Hepatic-directed Vesicle Insulin Add-on To Oral Antidiabetic Treatment In Patients With Type 2 Diabetes Mellitus

W. Geho, Len N Rosenberg, S. Schwartz, J. R. Lau, T. Gana
Published 2014 · Medicine

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Background: The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. Method: The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA1c 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). Results: All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Conclusions: Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.
This paper references
10.2337/diacare.20.3.292
NIDDM Patients' Fears and Hopes About Insulin Therapy: The basis of patient reluctance
L. Hunt (1997)
10.2337/DIACARE.25.2.330
Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57).
A. Wright (2002)
10.1177/193229680900300627
Hepatic-Directed Vesicle Insulin: A Review of Formulation Development and Preclinical Evaluation
W. Geho (2009)
10.1093/jn/131.11.3109S
Insulin, insulin-like growth factors and colon cancer: a review of the evidence.
E. Giovannucci (2001)
10.2337/DIACARE.29.04.06.DC05-0053
Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study.
M. Peyrot (2005)
A single-blind, placebo-controlled, food-dose timing trial of oral HDV-Insulin in patients with type 2 diabetes mellitus
B Geho (2009)
10.1001/JAMA.281.21.2005
Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.
R. Turner (1999)
10.1172/JCI108047
Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.
D. Horwitz (1975)
mellitus
PI Shishko (1985)
10.7326/0003-4819-124-1_PART_2-199601011-00004
Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus.
R. Henry (1996)
Hepatic-directed vesicle-insulin: evaluation of a novel oral and subcutaneous insulin delivery system in animal models of diabetes (Abstract). Diabetes. 2008;57(suppl 1):A126
B Geho (2008)
mellitus
JB Field (2009)
10.1177/030802265201500209
Abstract
Mustafa (1952)
10.2337/db07-0944
The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death
K. Chambers (2008)
10.1016/S1056-8727(01)00154-4
The effects of HDV-insulin on carbohydrate metabolism in Type 1 diabetic patients.
S. Davis (2001)
Insulin and risk of cardiovascular disease: a metaanalysis. Circulation
JB Ruige (1998)
10.1016/0026-0495(84)90128-8
Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans.
P. Bratusch-Marrain (1984)
10.1038/sj.ijo.0802173
When oral agents fail: practical barriers to starting insulin
M. Korytkowski (2002)
[Insulin extraction by the isolated perfused rat liver using infusion conditions of a biphasic insulin concentration profile].
H. Brömme (1984)
10.2337/DIABETES.54.6.1649
Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans.
J. Meier (2005)
10.2337/diab.41.9.1042
Comparison of Peripheral and Portal (Via the Umbilical Vein) Routes of Insulin Infusion in IDDM Patients
P. I. Shishko (1992)
10.1210/JCEM-56-6-1294
Hepatic removal of insulin in normal man: dose response to endogenous insulin secretion.
R. Eaton (1983)
10.1177/193229680900300323
Oral Insulin and Buccal Insulin: A Critical Reappraisal
L. Heinemann (2009)
10.1097/00019616-199911000-00013
Glycemic Control with Diet, Sulfonylurea, Metformin, or Insulin in Patients with Type 2 Diabetes Mellitus: Progressive Requirement for Multiple Therapies (UKPDS 49)
R. Turner (1999)
Banting lecture
GM Reaven (1988)
10.2174/1381612013397384
Alternative routes of administration as an approach to improve insulin therapy: update on dermal, oral, nasal and pulmonary insulin delivery.
L. Heinemann (2001)
10.2337/diab.19.5.302
Portal and Peripheral Vein Immunoreactive Insulin Concentrations Before and After Glucose Infusion
W. Blackard (1970)
10.2337/diab.37.12.1595
Role of Insulin Resistance in Human Disease
G. Reaven (1988)
10.11501/3107161
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus : a randomized prospective 6-year study
康生 大久保 (1995)
10.1152/AJPENDO.1983.244.6.E517
Splanchnic and renal metabolism of insulin in human subjects: a dose-response study.
E. Ferrannini (1983)
10.2337/diab.34.3.222
The Effect of Insulin Treatment on Insulin Secretion and Insulin Action in Type II Diabetes Mellitus
W. Garvey (1985)
mellitus ( Abstract )
WG Blackard (2008)
10.1177/193229680900300322
Oral Insulin: The Rationale for This Approach and Current Developments
E. Arbit (2009)
10.1046/j.1464-5491.2003.01076.x
Alternative routes of insulin delivery
D. Owens (2003)
10.1161/01.CIR.97.10.996
Insulin and risk of cardiovascular disease: a meta-analysis.
J. Ruige (1998)
10.2337/diabetes.37.12.1595
Banting lecture 1988. Role of insulin resistance in human disease.
G. Reaven (1988)
10.1016/S0140-6736(98)07019-6
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
UK Prospective Diabetes Study Group (1998)
A 2-week randomized, active comparator study of two HDV-Insulin routes (SC and oral) and SC human insulin in patients with type 1 diabetes mellitus (Abstract). Diabetes. 2008;57(suppl 1):A124
S Schwartz (2008)
Hepatic - directed vesicle - insulin : evaluation of a novel oral and subcutaneous insulin delivery system in animal models of
B Geho
10.2337/DIACARE.28.11.2673
Resistance to Insulin Therapy Among Patients and Providers Results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study
M. Peyrot (2005)
10.1007/BF00253736
Hepatic and peripheral insulin resistance: A common feature of Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetes mellitus
R. DeFronzo (2004)
10.1146/ANNUREV.ME.24.020173.001521
Extraction of insulin by liver.
J. Field (1973)



This paper is referenced by
Progress in Nanomedicine: Approved and Investigational Nanodrugs.
C. Ventola (2017)
10.1038/s41573-019-0053-0
Advances in oral peptide therapeutics
Daniel J. Drucker (2019)
10.1016/j.addr.2020.05.007
Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches.
D. Brayden (2020)
A REVIEW ON ORAL INSULIN
Aarti Khulbe (2015)
10.1007/978-3-030-11748-1_13
Peptide Drug Design for Diabetes and Related Metabolic Diseases
Niels C. Kaarsholm (2019)
10.1177/1932296819871947
Nanotechnology Approaches to Modulate Immune Responses to Cell-based Therapies for Type 1 Diabetes
S. Wiggins (2020)
10.1016/j.addr.2016.02.004
Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials.
T. A. Aguirre (2016)
10.3929/ethz-a-010735196
Amphiphilic nucleic acid conjugates for transfection of differentiated intestinal cells
E. V. Moroz (2016)
Progress in Nanomedicine: Approved and Investigational Nanodrugs.
Ventola Cl (2017)
10.1016/j.addr.2016.01.010
Oral delivery of macromolecular drugs: Where we are after almost 100years of attempts.
E. Moroz (2016)
10.1080/1061186X.2019.1669043
Protein drug delivery: current dosage form profile and formulation strategies
Danilo Costa Geraldes (2019)
10.1002/wnan.1416
Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials.
J. Caster (2017)
10.1007/978-981-15-4802-4
Applications of Nanomaterials in Human Health
F. Khan (2020)
10.1007/978-3-319-10939-8_3
Emerging Insulin Therapies
Winston Crasto (2016)
10.3390/pharmaceutics12080710
Insulin-Loaded Barium Salt Particles Facilitate Oral Delivery of Insulin in Diabetic Rats
Rahela Zaman (2020)
10.1016/J.JDDST.2017.06.018
Advances on the formulation of proteins using nanotechnologies
Irene Santalices (2017)
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